085 - A novel drug SP-8356 targeting CD147 suppresses pathological vascular remodeling via affecting vascular smooth muscle cell phenotype expression in atherosclerotic rat model (ID 26)
Abstract
Background and Aims
The switching of vascular smooth muscle cell (VSMC) phenotype plays key roles in neointimal hyperplasia and its related arterial stiffness. Cluster of differentiation 147 (CD147), a member of the immunoglobulin super family that induces the expression of matrix metalloproteinase-9 (MMP-9) by dimerization, may play important roles in the switching of VSMC phenotype and may therefore be an effective target for the treatment of neointimal hyperplasia. Here, we investigated whether a novel drug SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) targeting CD147 inhibitor could affects VSMC phenotype expression and inhibit neoitimal hyperplasia in atherosclerotic rat model.
Methods
The A10 VMSC cell lines were used for in-vitro experiment. Neointimal hyperplasia was generated in Sprague-Dawley rats by partial ligation of the right carotid artery combined with an atherogenic diet. Rosuvastatin was used for positive control drug. Rats were subdivided into vehicle and SP-8356 (50 mg/kg) groups. The drug was administrated via intraperitoneal injections for 4 weeks. Arterial stiffness was assessed by measuring pulse wave velocity using Doppler ultrasonography before sacrifice.
Results
SP-8356 suppressed CD147 dimerization thereby reducing MMP-9 activity, synthetic VSMC phenotype expression, and VSMC migration. SP-8356 also reduced neointimal hyperplasia and improved arterial stiffness in animal model. SP-8356 enhanced the expression of smooth muscle myosin heavy chain, but decreased the collagen type III and MMP-9 expression in the neointimal area.
Conclusions
SP-8356 affects VSMC phenotype modulation thereby reducing neointimal hyperplsaisa. Thus, SP-8356 could be a promising therapeutic drug for vascular remodeling disorders related with neointimal hyperplasia and arterial stiffness.
